FULL PAPER

Synthesis of Oxazolidinones by a Solid-Phase/Activation Cycloelimination(SP/ACE) Methodology

Peter ten Holte,[a] Bart C. J. van Esseveldt,[a] Lambertus Thijs,[a] and Binne Zwanenburg*[a]

Keywords: Oxazolidinones / Solid-phase synthesis / Cyclization / Cleavage reactions / Antibiotics

A versatile method for the solid-phase synthesis of oxazolidi-nones is described. An appropriate 1,2-diol is attached to im-mobilized sulfonyl chloride, resulting in the selective activa-tion of one of the alcohol functions. The subsequent reaction

Introduction

Oxazolidinones are synthetic antibacterials that exhibitactivity against many antibiotic-resistant strains of Gram-positive bacteria.[1] They represent the only completely newclass of antibiotics licensed over the past 30 years.[2] Struc-ture-activity relationship (SAR) studies have revealed themost important features that are responsible for their biolo-gical activity, as summarized in Figure 1.[3]

Figure 1. Structural entities that are essential and those that arevariable for biological activity

Despite the considerable synthetic attention given tothese 3,5-disubstituted 1,3-oxazolidin-2-ones during the lastdecade, the vast majority of reported synthetic routes arestill performed in solution.[4] This information encouragedus to develop a novel solid-phase synthetic route leading tooxazolidinones which possess the general structure that isnecessary for antibiotic activity (as in Figure 1). We reporthere on the synthesis of oxazolidinones by a solid-phase/activation cycloelimination (SP/ACE) process, which makesuse of an SN2-type cyclization/cleavage (C/C) strategy. SP/ACE enables the preparation of oxazolidinones by at-taching a 1,2-diol to immobilized sulfonyl chloride, fol-lowed by reaction with isocyanate, and subsequent base-promoted cycloelimination with concurrent detachmentfrom the resin (Scheme 1). Our approach enables the effici-

[a] Department of Organic Chemistry, NSR Institute forMolecular Structure, Design and Synthesis, University ofNijmegen,Toernooiveld 1, 6525 ED Nijmegen, The Netherlands ,Fax: (internat.) 131-24/365-3393E-mail: zwanenb@sci.kun.nl

Eur. J. Org. Chem. 2001, 296522969 WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001 14342193X/01/081522965 $ 17.501.50/0 2965

of the other alcohol group with an isocyanate, followed by abase-promoted cycloelimination gives an oxazolidinone. Byproper choice of isocyanates, functionalities can be intro-duced which are essential for antibiotic activity.

ent introduction of defined chirality at C-5 by employing a-mannitol-derived enantiomerically pure 1,2-diol.

Results and Discussion

SP/ACE: The Concept

To investigate the scope of this solid-phase/activationcycloelimination principle, a set of three commercially avail-able 1,2-diols (2a2c) were attached to the polymer-boundsulfonyl chloride 1[5,6] in a parallel fashion (Scheme 1), giv-ing the polymer-bound sulfonates 3a2c. In this manner, aselective activation of the primary alcohol was attained,leaving the secondary alcohol function untouched. The sub-sequent reaction of the secondary alcohol group with p-toluenesulfonyl isocyanate gave the highly activated carba-mates 4a2c, which appeared to be especially susceptible tobase-promoted cycloelimination. This nucleophilic cyclo-cleavage is exceptional, as it proceeds by direct SN2 substi-tution,[7] in contrast to the extensively studied nucleophilicremoval by means of an SAE-type reaction.[8] The cycloelim-ination was accomplished with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as the base and gave the oxazolidinones 5a2cin an overall yield of 39243%.[9]

Along with the target compounds 5a and 5b, the forma-tion of a minor amount (,1%) of the corresponding 3,4-disubstituted oxazolidinones was observed. These regioiso-mers, however, were readily removed by recrystallization ofthe products. Despite the ambident nucleophilic characterof the polymer-bound carbamates 4, O-alkylation was onlyobserved during the cycloelimination of 4c, giving the cor-responding cyclic carbonate by-product 9 (about 25%). Thisalternative mode of cyclization/cleavage can most likely beattributed to steric factors (R1 5 tBu).

Synthesis of the Target Oxazolidinones

The oxazolidinones 5d2g were synthesized by employingthe 1,2-diol 2d in the SP/ACE procedure (Scheme 1). Diol2d was prepared from commercially available solketal ac-cording to the literature.[10212] Tosylation of the alcoholgroup, followed by substitution with azide, and subsequentdeprotection, afforded 2d in good overall yield (68%). The

P. ten Holte, B. C. J. van Esseveldt, L. Thijs, B. ZwanenburgFULL PAPER

Scheme 1. Synthesis of substituted oxazolidinones by SP/ACE

coupling of diol 2d to the immobilized arenesulfonyl chlor-ide 1 was accomplished with triethylamine in dichlorome-thane. The remaining secondary alcohol was then reactedwith a series of N-aryl isocyanates, giving the polymer-bound N-aryl carbamates 4d2g. The lower reactivity ofaryl isocyanates compared to the aforementioned tosyl iso-cyanate necessitated the use of triethylamine (0.121 equiv.)to allow the reaction to occur. The carbamates preparedin this manner were then treated with DBN (2 equiv.) indichloromethane. Cyclization to oxazolidinones 5d2g oc-curred in spite of the less-activated N2H bond of the N-aryl carbamate. The observed overall yield of 5e (R 5 p-Ac-Ph) was disappointingly low (6%), which is most likelydue to the poor solubility of the isocyanate. However, theyield of the cycloeliminated compounds 5d, 5f and 5g wasmore satisfactory (32242%). The purity of the detachedmaterial was in all cases high (.85% by GC analysis).

The thus acquired N-aryl-5-azidomethyl oxazolidinones5d2g were expected to be suitable for conversion into thecorresponding N-aryl-5-amidomethyl oxazolidinones (as inFigure 1) by successive reduction and acylation of the azidegroup. For this reason, N-phenyl-5-azidomethyl oxazolidi-none 5d was subjected to catalytic hydrogenation [H2/Pd(C)] and subsequent acetylation (Ac2O/pyridine) giving6a (Scheme 2). These steps proceeded smoothly in goodoverall yield (90%). Additionally, a sample of 5d was hydro-genated and subsequently converted into the benz-amidomethyl-substituted oxazolidinone 6b underSchotten2Baumann conditions (80% overall; Scheme 2)showing that variation in the amidomethyl moiety can bereadily attained.

Enantiopure Oxazolidinones

Since compound 5d appeared to be an excellent candid-ate to be converted into the amidomethyl-substituted ox-

Eur. J. Org. Chem. 2001, 2965229692966

Scheme 2. Conversion of the azidomethyl moiety into amidome-thyl substituents

azolidinones 6, we decided to prepare N-aryl-5-azidomethyloxazolidinones with the correct and unambiguous stereo-chemistry (R-configuration) at C-5. The desired stereo-genicity can be introduced in the target oxazolidinones byemploying the optically pure 1,2-diol 7 (Scheme 3). Diol 7was prepared from S-(1)-solketal, analogous to the syn-thesis of racemic diol 2d.[10212] S-(1)-Solketal can be pre-pared by successive protection, oxidative cleavage (NaIO4)and subsequent reduction (NaBH4) of -mannitol as hasbeen reported previously.[13215] The optical rotation of theoxazolidinones 8a {[α]D20 5 2157 (c 5 1, ethanol)} and 8b{[α]D20 5 2150 (c 5 1, acetonitrile)} was found to be in

Scheme 3. Synthesis of enantiopure oxazolidinones by SP/ACE

Synthesis of Oxazolidinones FULL PAPERgood agreement with the values reported in the literature.[16]

Chiral HPLC of 8a (Chiralcel OD, 2-propanol/hexane,20:80) and 8b (Chiralpak AD, 2-propanol/hexane, 30:70),demonstrated that only one enantiomer was present in thesample, as was proved by simultaneous runs of thesesamples with the corresponding racemates 5d and 5e, whichshowed complete separation under these conditions.

Conclusion

The present study describes a convenient solid-phasemethod for the preparation of 3,5-disubstituted oxazolidin-2-ones employing the SP/ACE methodology. The synthesisof the target compounds by SP/ACE is accomplished withhigh purity and in good overall yields. Enantiopure prod-ucts are easily attained by using S-(1)-solketal as startingmaterial.

Experimental Section

General: Melting points were determined using a Reichert thermo-pan microscope and are uncorrected. Optical rotations were meas-ured with a Perkin2Elmer automatic polarimeter, model 241 MC,using concentrations c in g/100 mL at 20 °C in the solvents indic-ated. 1H and 13C NMR spectra were recorded with a Bruker AMX-500, a Bruker AM-400, or a Bruker AC-300 spectrometer inCDCl3. The chemical shift δ is denoted in ppm relative to the in-ternal standard (TMS for 1H NMR, CDCl3 for 13C NMR). FTIRspectra were recorded on an ATI Mattson 2 Genesis Series FTIRspectrophotometer. The wavenumbers are listed in cm21. For high-resolution mass spectra a double focussing VG7070E mass spectro-meter was used. Elemental analyses were performed using a CarloErba Instruments CHNS-O EA 1108 element analyzer. Polymerloading values, that were used as a starting point for following reac-tions, were established assuming quantitative preceding reactions.The overall yields of detached products were calculated accordingto the theoretical value, based on the loading of the original PS-TsCl (1.34 mmol/g). For this purpose, the amount of resin obtainedwas weighed after each reaction step and a known part of thisamount of product was then set up for the successive reaction.These values, together with the amounts of detached product, allowthe calculation of the correct overall yields.

Polymer-Bound Alcohols 3a2g. 2 General Procedure: Dichlorome-thane (5 mL), the 1,2-diol (3.35 mmol) and Et3N (0.37 mL,2.68 mmol) were added to the polymer-bound sulfonyl chloride 1(1.00 g, 1.34 mmol), and the mixture was allowed to stir overnightroom temperature. The resin was filtered and washed with dichloro-methane (50 mL, 33), methanol (50 mL, 33), and dichlorome-thane (50 mL, 33), and dried in vacuo for 6 h to give 3a2g. 2FTIR (KBr): ν̃ 5 3410 (OH), 2910 (C2H stretch), 1590 (arom.),1365 (2SO22), 1171 (2SO22).

Polymer-Bound Carbamates 4a2c. 2 General Procedure: Resin3a2c (1.15 mmol) was treated with tosyl isocyanate (0.35 mL,2.30 mmol) for 3 h at room temperature in dichloromethane(5 mL). The resin was filtered off, washed with methanol (50 mL,53), dichloromethane (50 mL, 33), methanol (50 mL, 53) anddichloromethane (50 mL, 33) and dried in vacuo for 6 h to affordcarbamates 4a2c. 2 FTIR (KBr): ν̃ 5 3300 (NH, broad), 2910(C2H stretch), 1740 (carbamate, linear), 1595 (arom.), 1365(2SO22), 1175 (2SO22).

Eur. J. Org. Chem. 2001, 296522969 2967

Polymer-Bound Carbamates 4d2g. 2 General Procedure: Resin3d2g (1.15 mmol) was treated with p-R-phenyl isocyanate (R 5 H,Ac, Br, NO2; 3.45 mmol) and triethylamine (0.02 mL, 0.14 mmol)overnight at room temperature in dichloromethane (5 mL). Theresin was filtered off, washed with dimethyl sulfoxide (dimethyl for-mamide in the case of R 5 Ac; 50 mL, 33), water (50 mL, 33),methanol (50 mL, 33), and dichloromethane (50 mL, 33) anddried in vacuo for 6 h to afford carbamates 4d2g. 2 FTIR (KBr):ν̃ 5 3300 (NH, broad), 2915 (C2H stretch), 2100 (N3) 1700 (carba-mate, linear), 1680 (C5O for R 5 Ac) 1590 (arom.), 1365(2SO22), 1175 (2SO22).

Cycloelimination to 3,5-Disubstituted 1,3-Oxazolidin-2-ones 5a2g.2 General Procedure: A sample of 4a2g (1.00 mmol) was sus-pended in dichloromethane (5 mL) and DBN (0.14 mL, 1.13 mmol)was added. The mixture was stirred at room temperature for 2 hand the resin was filtered, washed with dichloromethane (50 mL,33), methanol (50 mL, 33), dichloromethane (50 mL, 33), andmethanol (50 mL, 33). The filtrate was concentrated under re-duced pressure, and filtered through a short plug of silica gel (ethylacetate/heptane, 1:1). Evaporation of the solvent gave oxazolidi-nones 5a2f as a white solid and 5g as a slightly yellow solid. Crys-tallization of the product (5a2c: ethyl acetate/hexane, 5d2g: eth-anol/hexane) gave pure 5a2f as colorless crystals and 5g as slightlyyellow crystals. The polymer-supported sulfonyl chloride startingmaterial 1 could be regenerated by treatment of the remaining poly-mer with 1 sulfuric acid, followed by reaction with thionyl chlor-ide (3 equiv.) in DMF.[4b]

5-Methyl-3-tosyl-1,3-oxazolidin-2-one (5a): Yield 112 mg(0.44 mmol, 39% overall) white solid. Colorless crystals from ethylacetate/hexane; m.p. 1442145 °C. 2 1H NMR (CDCl3, 300 MHz)δ 5 1.42 (d, J 5 6.3 Hz, 3 H), 2.46 (s, 3 H), 3.57 (dd, part of ABX,JAB 5 9.1 Hz, JBX 5 7.1 Hz, 1 H), 4.14 (dd, part of ABX, JAB 5

9.1 Hz, JAX 5 7.8 Hz, 1 H), 4.69 (m, part of ABX, 1 H), 7.37 (d,J 5 8.3 Hz, 2 H), 7.93 (d, J 5 8.3 Hz, 2 H). 2 13C NMR (CDCl3,75 MHz): δ 5 19.78, 21.62, 50.91, 71.18, 128.15, 129.84, 133.82,145.67, 151.61. 2 MS (CI): m/z 5 256 (14) [M1 1 1], 191 (34)[M1 2 SO2], 155 (13) [C7H7SO2], 91 (100) [C7H7]. 2 C11H13NO4S(255.29): calcd. C 51.75, H 5.13, N 5.49; found C 51.75, H 4.97,N 5.55.

5-Ethyl-3-tosyl-1,3-oxazolidin-2-one (5b): Yield 122 mg (0.45 mmol,40% overall) white solid. Colorless crystals from ethyl acetate/hex-ane; m.p. 1162118 °C. 2 1H NMR (CDCl3, 300 MHz) δ 5 0.95(t, J 5 7.4 Hz, 3 H), 1.72 (m, 2 H), 2.45 (s, 3 H), 3.62 (dd, part ofABX, JAB 5 9.1 Hz, JBX 5 7.1 Hz, 1 H), 4.12 (dd, part of ABX,JAB 5 9.1 Hz, JAX 5 8.0 Hz, 1 H), 4.49 (m, part of ABX, 1 H),7.37 (d, J 5 8.4 Hz, 2 H), 7.93 (d, J 5 8.4 Hz, 2 H). 2 13C NMR(CDCl3, 75 MHz) δ 5 8.33, 21.52, 27.11, 49.09, 75.56, 127.99,129.75, 133.79, 145.59, 151.60. 2 MS (CI): m/z 5 270 (9) [M1 1

1], 205 (21) [M1 2 SO2], 155 (28) [C7H7SO2], 91 (100) [C7H7]. 2

C12H15NO4S (269.31): calcd. C 53.52, H 5.61, N 5.20; found C53.14, H 5.59, N 4.92.

5-tert-Butyl-3-tosyl-1,3-oxazolidin-2-one (5c): Yield 126 mg(0.49 mmol, consisting of both 5c (75%) and cyclic carbonate(25%), 43% overall) white solid. Colorless crystals of 5c from ethylacetate/hexane; m.p. 1212122 °C. 2 1H NMR (CDCl3, 300 MHz)δ 5 0.89 (s, 9 H), 2.45 (s, 3 H), 3.75 (dd, part of ABX, JAB 5

9.4 Hz, JBX 5 7.5 Hz, 1 H), 3.98 (dd, part of ABX, JAB 5 9.4 Hz,JAX 5 8.6 Hz, 1 H), 4.22 (dd, part of ABX, JAX 5 8.6 Hz, JBX 5

7.5 Hz, 1 H), 7.36 (d, J 5 8.4 Hz, 2 H), 7.93 (d, J 5 8.4 Hz, 2 H).2 13C NMR (CDCl3, 75 MHz) δ 5 21.63, 24.00, 33.64, 45.42,81.13, 128.02, 129.81, 134.04, 145.63, 151.73. 2 MS (CI): m/z 5

P. ten Holte, B. C. J. van Esseveldt, L. Thijs, B. ZwanenburgFULL PAPER298 (43) [M1 1 1], 233 (29) [M1 2 SO2], 155 (68) [C7H7SO2], 91(100) [C7H7]. 2 C14H19NO4S (297.37): calcd. C 56.55, H 6.44, N4.71; found C 56.78, H 6.58, N 4.73.

5-Azidomethyl-3-phenyl-1,3-oxazolidin-2-one (5d): Yield 94 mg(0.43 mmol, 40% overall) white solid. Colorless crystals from eth-anol/hexane; m.p. 82284 °C. 2 1H NMR (CDCl3, 400 MHz) δ 5

3.60 (dd, part of ABX, JAB 5 13.2 Hz, JBX 5 4.5 Hz, 1 H), 3.69(dd, part of ABX, JAB 5 13.2 Hz, JAX 5 4.7 Hz, 1 H), 3.87 (dd,part of ABX, JAB 5 9.0 Hz, JBX 5 6.2 Hz, 1 H), 4.10 (t, part ofABX, JAB 5 JAX 5 9.0 Hz, 1 H), 4.78 (m, part of ABX, 1 H), 7.16(t, J 5 7.4 Hz, 1 H), 7.39 (t, J 5 8.0 Hz, 2 H), 7.54 (d, J 5 8.1 Hz,1 H). 2 13C NMR (CDCl3, 100 MHz) δ 5 47.5, 53.1, 70.6, 118.3,124.4, 129.1, 137.9, 153.9. 2 MS (CI): m/z 5 190 (20) [M1 2 N2],71 (44) [C3H5NO], 43 (100) [C2H3O]. 2 C10H10N4O2 (218.21):calcd. C 55.04, H 4.62, N 25.68; found C 55.06, H 4.58, N 25.32.Spectroscopic data are in agreement with those reported previ-ously.[16]

3-p-Acetylphenyl-5-azidomethyl-1,3-oxazolidin-2-one (5e): Yield17 mg (0.07 mmol, 6% overall) white solid. Colorless crystals fromethanol/hexane; m.p. 80281 °C. 2 1H NMR (CDCl3, 400 MHz)δ 5 2.59 (s, 3 H), 3.62 (dd, part of ABX, JAB 5 13.3 Hz, JBX 5

4.3 Hz, 1 H), 3.74 (dd, part of ABX, JAB 5 13.3 Hz, JAX 5 4.4 Hz,1 H), 3.92 (dd, part of ABX, JAB 5 9.1 Hz, JBX 5 6.2 Hz, 1 H),4.15 (t, part of ABX, JAB 5 JAX 5 9.1 Hz, 1 H), 4.83 (m, part ofABX, 1 H), 7.65 (d, J 5 8.9 Hz, 2 H), 7.98 (d, J 5 8.9 Hz, 2 H).2 13C NMR (CDCl3, 100 MHz) δ 5 26.4, 47.1, 52.9, 70.7, 117.3,129.6, 132.7, 141.9, 153.6, 196.8. 2 MS (CI): m/z 5 232 (15) [M1

2 N2], 71 (47) [C3H5NO], 43 (100) [C2H3O]. 2 C12H12N4O3

(260.25): calcd. C 55.38, H 4.65, N 21.53; found C 55.03, H 4.44,N 21.48. Spectroscopic data are in agreement with those reportedpreviously.[17]

5-Azidomethyl-3-p-bromophenyl-1,3-oxazolidin-2-one (5f): Yield138 mg (0.46 mmol, 42% overall) white solid. Colorless crystalsfrom ethanol/hexane; m.p. 92293 °C. 2 1H NMR (CDCl3,400 MHz) δ 5 3.58 (dd, part of ABX, JAB 5 13.2 Hz, JBX 5

4.38 Hz, 1 H), 3.69 (dd, part of ABX, JAB 5 13.2 Hz, JAX 5

4.6 Hz, 1 H), 3.84 (dd, part of ABX, JAB 5 8.9 Hz, JBX 5 6.2 Hz,1 H), 4.07 (t, part of ABX, JAB 5 JAX 5 8.9 Hz, 1 H), 4.79 (m,part of ABX, 1 H), 7.44 (d, J 5 9.0 Hz, 2 H), 7.50 (d, J 5 9.0 Hz,2 H). 2 13C NMR (CDCl3, 100 MHz) δ 5 47.3, 53.0, 70.6, 117.2,119.7, 132.1, 137.0, 153.7. 2 MS (CI): m/z 5 268 (17) [M1 2 N2],71 (51) [C3H5NO], 43 (100) [C2H3O]. 2 HRMS (EI): m/z 5

295.9905 (C10H9BrN4O2 requires 295.9909).[18]

5-Azidomethyl-3-p-nitrophenyl-1,3-oxazolidin-2-one (5g): Yield98 mg (0.37 mmol, 32% overall) slightly yellow solid. Slightly yel-low crystals from ethanol/hexane; m.p. 1152116 °C. 2 1H NMR(CDCl3, 300 MHz) δ 5 3.65 (dd, part of ABX, JAB 5 13.4 Hz,JBX 5 4.2 Hz, 1 H), 3.79 (dd, part of ABX, JAB 5 13.4 Hz, JAX 5

4.2 Hz, 1 H), 3.96 (dd, part of ABX, JAB 5 9.1 Hz, JBX 5 6.2 Hz,1 H), 4.19 (dd, part of ABX, JAB 5 JAX 5 9.0 Hz, 1 H), 4.89 (m,part of ABX, 1 H), 7.73 (d, J 5 9.3 Hz, 2 H), 8.24 (d, J 5 9.3 Hz,2 H). 2 13C NMR (CDCl3, 75 MHz) δ 5 47.0, 52.8, 70.8, 117.4,119.9, 124.9, 125.1, 153.4. 2 MS (CI): m/z 5 235 (18) [M1 2 N2],71 (37) [C3H5NO], 43 (100) [C2H3O]. 2 C10H9N5O4 (263.21):calcd. C 45.63, H 3.45, N 26.61; found C 45.79, H 3.42, N 26.55.2 HRMS (EI): m/z 5 263.0651 (C10H9N5O4 requires 263.0655).

5-Acetamidomethyl-3-phenyl-1,3-oxazolidin-2-one (6a): A sample of5d (62 mg, 0.28 mmol) was dissolved in methanol (10 mL) and pal-ladium (10% on activated carbon; 12 mg, 0.01 mmol Pd) was addedunder nitrogen atmosphere. Subsequently, the mixture was shakenunder a hydrogen atmosphere (1 h) and filtered through a plug of

Eur. J. Org. Chem. 2001, 2965229692968

hyflo. The solvent was removed under reduced pressure giving theprimary amine as a colorless oil (99%), which was dissolved in amixture of pyridine (0.5 mL) and acetic anhydride (0.05 mL,0.53 mmol), and stirred at room temperature (1 h). Ice (25 mL) andaqueous HCl (36%; 0.6 mL, 6 mmol) were added, and the mixturewas extracted with dichloromethane (53 20 mL). The organic frac-tions were collected, dried (Na2SO4) and concentrated giving 60 mg(90% overall) of 6a as a white solid. Colorless crystals from ethanol:m.p. 1302131 °C. 2 1H NMR (CDCl3, 300 MHz) δ 5 2.01 (s, 3H), 3.64 (m, 2 H), 3.81 (dd, part of ABX, JAB 5 9.2 Hz, JBX 5

6.8 Hz, 1 H), 4.06 (dd, part of ABX, JAB 5 JAX 5 9.2 Hz, 1 H),4.78 (m, 1 H), 6.60 (m, 1 H), 7.15 (t, J 5 7.4 Hz, 1 H), 7.37 (t, J 5

8.6 Hz, 2 H), 7.50 (d, J 5 8.4 Hz, 2 H). 2 13C NMR (CDCl3,75 MHz) δ 5 23.0, 41.9, 47.5, 72.0, 118.4, 124.3, 129.1, 137.8,154.6, 171.2. 2 MS (CI): m/z 5 235 (7) [M1 1 1], 190 (18) [M1

2 CO2], 43 (100) [CH3CO]. 2 C12H14N2O3 (234.25): calcd. C61.53, H 6.02, N 11.96; found C 61.36, H 5.79, N 11.62. Spectro-scopic data are in agreement with those reported previously.[16]

5-Benzamidomethyl-3-phenyl-1,3-oxazolidin-2-one (6b): A sample of5d (151 mg, 0.68 mmol) was dissolved in methanol (10 mL) andpalladium (10% on activated carbon; 12 mg, 0.01 mmol Pd) wasadded under nitrogen atmosphere. Subsequently, the mixture wasshaken under a hydrogen atmosphere (1 h) and filtered through aplug of hyflo. The solvent was removed under reduced pressuregiving the primary amine as a colorless oil (99%). The amine andbenzoyl chloride (0.09 mL, 0.77 mmol) were dissolved in 10% aque-ous NaOH (8 mL), and the solution was stirred vigorously (15min.) in a sealed vessel. The white precipitate was filtered off, rinsedwith water, and dried in vacuo yielding 162 mg (80%) of 6b as awhite solid. Colorless crystals from ethanol; m.p. 168 °C. 2 1HNMR (CDCl3, 500 MHz) δ 5 3.80 (ddd, part of ABMX, JAB 5

14.7 Hz, JBM 5 JBX 5 6.1 Hz, 1 H), 3.88 (dd, part of ABX, JAB 5

9.1 Hz, JBX 5 6.7 Hz, 1 H), 3.94 (ddd, part of ABMX, JAB 5

14.7 Hz, JAM 5 3.4 Hz, JAX 5 6.4 Hz, 1 H), 4.11 (dd, part of ABX,JAB 5 JAX 5 9.1 Hz, 1 H), 4.88 (m, 1 H), 6.94 (t, J 5 6.4 Hz, 1H), 7.13 (t, J 5 7.5 Hz, 1 H), 7.35 (t, J 5 8.0 Hz, 2 H), 7.41 (t,J 5 8.0 Hz, 2 H), 7.50 (m, 3 H), 7.78 (d, J 5 7.0 Hz, 2 H). 2 13CNMR (CDCl3, 75 MHz) δ 5 42.5, 47.7, 72.0, 118.4, 124.3, 127.1,128.6, 129.1, 131.9, 133.5, 137.8, 154.5, 168.3. 2 MS (CI): m/z 5

297 (4) [M1 1 1], 252 (15) [M1 2 CO2], 105 (90) [C6H5CO], 77(100) [C6H5]. 2 C17H16N2O3 (296.32): calcd. C 68.91, H 5.44, N9.45; found C 68.55, H 5.16, N 9.07. 2 HRMS (EI): m/z 5

296.1162 (C17H16N2O3 requires 296.1161).

(R)-5-Azidomethyl-3-phenyl-1,3-oxazolidin-2-one (8a): Yield 89 mg(0.41 mmol, 38% overall) white solid. Colorless crystals from ethylacetate/hexane; m.p. 76278 °C. 2 [α]D20 5 2157 (c 5 1, ethanol).1H and 13C NMR spectra are identical to those of 5d. Meltingpoint and spectroscopic data are in agreement with those re-ported previously.[16]

(R)-5-Azidomethyl-3-p-acetylphenyl-1,3-oxazolidin-2-one (8b): Yield16 mg (0.06 mmol, 5% overall) white solid. Colorless crystals fromethyl acetate/hexane; m.p. 79281 °C. 2 [α]D20 5 2150 (c 5 1, ace-tonitrile). 1H and 13C NMR spectra are identical to those of 5e.Melting point and spectroscopic data are in agreement with thosereported previously.[16,17]

[1] D. L. Shinabarger, K. R. Marotti, R. W. Murray, A. H. Lin,E. P. Melchior, S. M. Swaney, D. S. Dunyak, W. F. Demyan, J.M. Buysse, Antimicrob. Agents Chemother. 1997, 41,213222136.

Synthesis of Oxazolidinones FULL PAPER[2] Chem. Eng. News, May 29, 2000, p. 12.[3] A general structure-activity relationship was defined by

Brickner: S. J. Brickner, D. K. Hutchinson, M. R. Barbachyn,P. R. Manninen, D. A. Ulanowicz, S. A. Garmon, K. C. Grega,S. K. Hendges, D. S. Toops, C. W. Ford, G. E. Zurenko, J.Med. Chem. 1996, 39, 6732679.

[4] To the best of our knowledge, only two papers on the solid-phase synthesis of 3,5-disubstituted 1,3-oxazolidin-2-ones haveappeared in the literature:[4a] H.-P. Buchstaller, Tetrahedron1998, 54, 346523470. 2 [4b] A first outline of our methodologywas published in a previous communication: P. ten Holte, L.Thijs, B. Zwanenburg, Tetrahedron Lett. 1998, 39, 740727410.

[5] PS-TsCl, 1.34 mmol/g. Purchased from Argonaut Technolo-gies Inc.

[6] For recent reviews on linkers for SPOS, see: [6a] I. W. James,Tetrahedron 1999, 55, 485524946. 2 [6b] F. Guillier, D. Orain,M. Bradley, Chem. Rev. 2000, 100, 209122157.

[7] Only a few other examples of SN2-type cyclization/cleavagesare known: [7a] T. Takahashi, S. Tomida, H. Inoue, T. Doi, Syn-lett 1998, 126121263. 2 [7b] M. C. Pirrung, L. N. Tumey, J.Comb. Chem. 2000, 2, 6752680.

[8] For a recent review on cyclization/cleavage methodologies, see:J. H. van Maarseveen, Comb. Chem. High Throughput Screen-ing 1998, 1, 1852214.

[9] The average overall yield of 70% reported in the previous com-munication (ref. 4b) was obtained in a multi-gram scale experi-

Eur. J. Org. Chem. 2001, 296522969 2969

ment with Dowex 50X22400 ion-exchange resin-derived sul-fonyl chloride.

[10] E. Baer, H. O. L. Fischer, J. Am. Chem. Soc. 1948, 70,6092610.

[11] U. Schmidt, R. Meyer, V. Leitenberger, F. Stäbler, A. Lieberk-necht, Synthesis 1991, 4092413.

[12] S. F. Martin, Y.-L. Wong, A. S. Wagman, J. Org. Chem. 1994,59, 482124831.

[13] C. R. Schmid, J. D. Bryant, M. Dowlatzedah, J. L. Phillips, D.E. Prather, R. D. Schantz, N. L. Sear, C. S. Vianco, J. Org.Chem. 1991, 56, 405624058.

[14] G. J. F. Chittenden, Carbohydr. Res. 1991, 222, 2832287.[15] S. Takano, H. Numata, K. Ogasawara, Heterocycles 1982, 19,

3272328.[16] W. A. Gregory, D. R. Brittelli, C.-L. J. Wang, M. A. Wuonola,

R. J. McRipley, D. C. Eustice, V. S. Eberly, P. T. Bartholomew,A. M. Slee, M. Forbes, J. Med. Chem. 1989, 32, 167321681.Optical rotations reported: Compound 8a: [α]25

D 5 2160.0 60.9 (c 5 0.93, ethanol); compound 8b: [α]25

D 5 2150.0 6 0.9(c 5 0.93, acetonitrile).

[17] C.-L. J. Wang, W. A. Gregory, M. A. Wuonola, Tetrahedron1989, 45, 132321326.

[18] The 400-MHz 1H NMR and 100-MHz 13C NMR of sample 5fdid not reveal any impurities; nevertheless no reliable elementalanalysis of compound 5f could be obtained.

Received February 12, 2001[O01067]